Promising but Scarce

Of all the drugs that physicians now use to treat various forms of cancer, by far the most promising is the enzyme "L"-asparaginase. It is the first that has been found to deprive some types of cancer cells of a substance that they cannot make but must have.

This substance is the amino acid, "L"-asparagine. Normal cells also use it, and can apparently make it themselves.

So, unfortunately, can certain cancer cells, which explains why asparaginase cannot be effective against all kinds of cancer. But it has the enormous ad vantage that whereas other anticancer drugs may damage normal cells as well as cancer cells, asparaginase is highly selective. It deprives only some vulnerable cancer cells of asparagine, doing no harm to normal cells.

Tests so far show that the enzyme works best against certain forms of leukemia. But research physicians treating patients with asparaginase are laboring under grave handicaps. For one, much of the available supply is too impure to be given safely to patients already suffering from acute leukemia.

For another, asparaginase is still forbiddingly expensive, and scarce.

One Optimal Dose. The impurities, which cause fever and allergic reactions, are not the manufacturers' fault, says Dr. Harold Campbell, who is working on improved purification methods.

They are produced by the colon bacteria from which asparaginase is extracted. Expense and scarcity result from the fact that a 400-gallon fermenter such as those used by New Jersey's Worthington Biochemical Corp. produces 44 Ibs. of "wet-weight" E. coli bacteria. From this only 1/30 of an ounce of asparaginase can be extracted. Such an amount, says Dr. Lloyd J. Old of Manhattan's Memorial Sloan-Kettering Cancer Center, is enough to treat two children or one adult for only three weeks. Of 81 patients with various kinds of cancer treated so far at Memorial with asparaginase, none have received what the doctors believe may be the optimal dose.

Despite the limited supplies, early results are encouraging. Dr. Herbert F. Oettgen reports that of 27 patients with acute lymphocytic leukemia treated by Memorial physicians, 16 (including 13 children) have had favorable responses followed by relapses. The same is true of leukemic mice; if they receive doses in the same proportion (by body weight) as human patients get, their disease is arrested for a while, then it recurs. But if mice are given hundredfold greater doses, some are cured, says Dr. Ed ward A. Boyse. The Memorial doctors want to get enough asparaginase to try such massive doses on humans. In a few cases treated for some other forms of leukemia and in different types of cancer, the response rate is near zero, with one striking exception. A man who had several melanoma deposits under his skin was given asparaginase for three weeks; now, four months later, he appears free of this virulent disease. In four other melanoma cases there was no response.

Two Enzymes. Why asparaginase is effective against some cancer cells and not others has just been explained by a research team in the biochemistry department at Cornell University Medical College and at Sloan-Kettering. All cells need the amino acid asparagine, and to make it they need the enzyme asparagine synthetase. If they lack this, they are dependent on borrowing asparagine from other cells, and asparaginase knocks out the floating supply, leaving none to be borrowed. Cancer cells that happen to have the synthetase enzyme are not affected by asparaginase, so the chemical would be wasted in attempts to treat patients with cancerous cells of this type.

How many cancers of different types could be usefully attacked can be determined only by elaborate additional testing. To boost asparaginase research directly, the National Institutes of Health has put up $571,000 in grants, including $450,000 to E. R. Squibb & Sons; Sloan-Kettering is spending $450,000 a year, almost half of which comes from NIH. Worthington Biochemical has increased its production by converting a new building to E. coli fermentation and asparaginase extraction. It has also licensed Merck & Co. to use its processes in their bigger facilities, and companies in Europe and Japan have begun experimental production and purity testing.

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